This invention relates to certain novel compounds and derivatives thereof, their synthesis, and their use as alpha 1a adrenoceptor antagonists. More particularly, the compounds of the present invention are useful for treating benign prostatic hyperplasia (BPH).
Human adrenergic receptors are integral membrane proteins which have been classified into two broad classes, the alpha and the beta adrenergic receptors. Both types mediate the action of the peripheral sympathetic nervous system upon binding of catecholamines, norepinephrine and epinephrine.
Norepinephrine is produced by adrenergic nerve endings, while epinephrine is produced by the adrenal medulla. The binding affinity of adrenergic receptors for these compounds forms one basis of the classification: alpha receptors bind norepinephrine more strongly than epinephrine and much more strongly than the synthetic compound isoproterenol. The binding affinity of these hormones is reversed for the beta receptors. In many tissues, the functional responses, such as smooth muscle contraction, induced by alpha receptor activation are opposed to responses induced by beta receptor binding.
Subsequently, the functional distinction between alpha and beta receptors was further highlighted and refined by the pharmacological characterization of these receptors from various animal and tissue sources. As a result, alpha and beta adrenergic receptors were farther subdivided into alpha 1, alpha 2, xcex21, and xcex22 subtypes. Functional differences between alpha 1 and alpha 2 receptors have been recognized, and compounds which exhibit selective binding between these two subtypes have been developed.
For a general background on the alpha adrenergic receptors, the reader""s attention is directed to Robert R. Ruffolo, Jr.,
The cloning, sequencing and expression of alpha receptor subtypes from animal tissues has led to the subclassification of the alpha 1 receptors into alpha 1d (formerly known as alpha 1a or 1a/1d), alpha 1b and alpha 1a (formerly known as alpha 1c) subtypes. Each alpha 1 receptor subtype exhibits its own pharmacologic and tissue specificities. The designation xe2x80x9calpha 1axe2x80x9d is the appellation recently approved by the IUPHAR Nomenclature Committee for the previously designated xe2x80x9calpha 1cxe2x80x9d cloned subtype as outlined in the 1995 Receptor and Ion Channel Nomenclature Supplement (Watson and Girdlestone, 1995). The designation alpha 1a is used throughout this application to refer to this subtype. At the same time, the receptor formerly designated alpha 1a was renamed alpha 1d. The new nomenclature is used throughout this application. Stable cell lines expressing these alpha 1 receptor subtypes are referred to herein; however, these cell lines were deposited with the American Type Culture Collection (ATCC) under the old nomenclature. For a review of the classification of alpha 1 adrenoceptor subtypes, see, Martin C. Michel, et al., Naunyn-Schmiedeberg""s Arch. Phanmacol. (1995) 352:1-10.
The differences in the alpha adrenergic receptor subtypes have relevance in pathophysiologic conditions. Benign prostatic hyperplasia, also known as benign prostatic hypertrophy or BPH, is an illness typically affecting men over fifty years of age, increasing in severity with increasing age. The symptoms of the condition include, but are not limited to, increased difficulty in urination and sexual dysfunction. These symptoms are induced by enlargement, or hyperplasia, of the prostate gland. As the prostate increases in size, it impinges on free-flow of fluids through the male urethra. Concommitantly, the increased noradrenergic innervation of the enlarged prostate leads to an increased adrenergic tone of the bladder neck and urethra, further restricting the flow of urine through the urethra.
In benign prostatic hyperplasia, the male hormone 5-alpha-dihydrotestosterone has been identified as the principal culprit. The continual production of 5a-dihydrotestosterone by the male testes induces incremental growth of the prostate gland throughout the life of the male. Beyond the age of about fifty years, in many men, this enlarged gland begins to obstruct the urethra with the pathologic symptoms noted above.
The elucidation of the mechanism summarized above has resulted in the recent development of effective agents to control, and in many cases reverse, the pernicious advance of BPH. In the forefront of these agents is Merck and Co., Inc.s"" product PROSCAR(copyright) (finasteride). The effect of this compound is to inhibit the enzyme testosterone 5-a reductase, which converts testosterone into 5a-dihydrotesterone, resulting in a reduced rate of prostatic enlargement, and often reduction in prostatic mass.
The development of such agents as PROSCAR(copyright) bodes well for the long-term control of BPH. However, as may be appreciated from the lengthy development of the syndrome, its reversal also is not immediate. In the interim, those males suffering with BPH continue to suffer, and may in fact lose hope that the agents are working sufficiently rapidly.
In response to this problem, one solution is to identify pharmaceutically active compounds which complement slower-acting therapeutics by providing acute relief. Agents which induce relaxation of the lower urinary tract tissue, by binding to alpha 1 adrenergic receptors, thus reducing the increased adrenergic tone due to the disease, would be good candidates for this activity. Thus, one such agent is alfuzosin, which is reported in EP 0 204597 to induce urination in cases of prostatic hyperplasia. Likewise, in WO 92/00073, the selective ability of the R(+) enantiomer of terazosin to bind to adrenergic receptors of the alpha1 subtype was reported. In addition, in WO 92/16213, combinations of Sa-reductase inhibitory compounds and alpha1-adrenergic receptor blockers (terazosin, doxazosin, prazosin, bunazosin, indoramin, alfulzosin) were disclosed. However, no information as to the alpha 1d, alpha 1b, or alpha 1a subtype specificity of these compounds was provided as this data and its relevancy to the treatment of BPH was not known. Current therapy for BPH uses existing non-selective alpha 1 antagonists such as prazosin (Minipress, Pfizer), Terazosin (Hytrin, Abbott) or doxazosin mesylate (Cardura, Pfizer). These non-selective antagonists suffer from side effects related to antagonism of the alpha 1d and alpha 1b receptors in the peripheral vasculature, e.g., hypotension and syncope.
The recent cloning of the human alpha 1a adrenergic receptor (ATCC CRL 11140) and the use of a screening assay utilizing the cloned human alpha 1a receptor enables identification of compounds which specifically interact with the human alpha 1a adrenergic receptor. [PCT International Application Publication Nos. WO94/08040, published Apr. 14, 1994 and WO94/10989, published May 26, 1994] As disclosed in the instant patent disclosure, a cloned human alpha 1a adrenergic receptor and a method for identifying compounds which bind the human alpha 1a receptor has now made possible the identification of selective human alpha 1a adrenergic receptor antagonists useful for treating BPH.
WO 96/14846, published May 23, 1996, discloses a broad genus of dihydropyrimidine compounds and proposes their use as selective antagonists for human alpha 1a receptors. Compounds were assayed using cloned human alpha adrenergic receptors, and certain of the compounds so assayed were disclosed to be selective alpha 1a antagonists.
The instant application presents novel dihydropyrimidine compounds (generally referred to herein as xe2x80x9creverse dihydropyrimidinonesxe2x80x9d as described below) which are useful as selective alpha 1a antagonists and which typically exhibit high potency and high selectivity in screening assays for alpha 1a receptor binding and in assays for determining selective binding to alpha 1a receptors over alpha 1b and 1d receptors. These compounds are further tested for binding to other human alpha 1 receptor subtypes, as well as counterscreened against other types of receptors (e.g., alpha 2), thereby further defining the specificity of the compounds of the present invention for the human alpha 1a adrenergic receptor.
The compounds of the present invention are useful as agents for treating BPH in animals, preferably mammals, especially humans. The alpha 1a adrenergic receptor antagonist compounds of the invention are also useful for relaxing lower urinary tract tissue in animals, preferably mammals, especially humans.
The present invention provides compounds for the treatment of urinary obstruction caused by benign prostatic hyperplasia (BPH). The compounds antagonize the human alpha 1a adrenergic receptor at nanomolar and subnanomolar concentrations while typically exhibiting at least ten fold lower affinity for the alpha 1d and alpha 1b human adrenergic receptors and many other G-protein coupled receptors. This invention has the advantage over non-selective alpha 1 adrenoceptor antagonists of reduced side effects related to peripheral adrenergic blockade. Such side effects include hypotension, syncope, lethargy, etc.
The present invention is a compound of formula (I): 
wherein R1 is selected from phenyl, substituted phenyl, pyridyl, and substituted pyridyl, wherein the substituents on the phenyl or the pyridyl are independently selected from F, Cl, Br, I, (CH2)0-4CF3, CN, NO2, Ra, and ORa;
R10 is selected from H, OH, CN, Rb, ORb, (CH2)1-4ORb and (CH2)0-4CF3;
m is an integer of from 0 to 2;
L is selected from (CH2)k, (CHR2)k, CR8R9(CH2)kxe2x88x921, (CH2)kxe2x88x921CR8R9, CH2CR8R9CH2, CH2CH2CR8R9CH2, and CH2CR8R9CH2CH2;
R2 is selected from RC and (CH2)0-4CF3;
k is an integer of from 2 to 4;
R4 is selected from H, Rd and (CH2)0-4CF3;
R5 is selected from H, Re, (CH2)1-4ORe, and (CH2)1-4CF3;
R6 is selected from H and Rf;
R7 is selected from H, Rg, (CH2)1-4ORg, C(xe2x95x90O)ORg, C(xe2x95x90O)Rg and (CH2)0-4CF3;
R8 and R9 are each independently selected from Rc and (CH2)0-4CF3;
each X is independently selected from F, Cl, Br, I, CN and Rh;
Ra, Rd, Re, Rf, Rg and Rh are each independently selected from C1 to C6 alkyl;
Rb and Rc are independently selected from C1 to C6 alkyl and C3 to C7 cyclic alkyl;
and q is an integer of from 0 to 4, provided that when R7 is CORg or COORg, R1 is not phenyl; or
a pharmaceutically acceptable salt thereof.
A first embodiment of the invention is a compound of formula (I), wherein R1 is selected from phenyl, mono-, di- or tri-substituted phenyl, pyridyl, and mono-, di-, or tri-substituted pyridyl, wherein the substituents on the phenyl or the pyridyl are independently selected from F, Cl, Br, I, CN and Ra;
R10 is selected from H, OH, CN, Rb and ORb;
R2 is selected from H and Re;
R4 is selected from H and Rd;
R5 is selected from H, Re and (CH2)1-4ORe;
R7 is selected from H, Rg, (CH2)1-4ORg, C(xe2x95x90O)ORg and C(xe2x95x90O)Rg;
R8 and R9 are each Rc;
Ra, Rb, Rc, Rd, Re, Rf, Rg and Rh are each independently selected from C1 to C4 alkyl;
q is an integer of from 0 to 3, provided that when R7 is CORg or COORg, R1 is not phenyl;
all other variables are as previously defined; or
a pharmaceutically acceptable salt thereof.
A second embodiment of the invention is a compound of formula (I), wherein R7 is selected from H, Rg and (CH2)1-4ORg;
q is an integer of from0to 3; and
all other variables are as defined in the first embodiment; or
a pharmaceutically acceptable salt thereof.
A third embodiment of the invention is a compound of formula (I), wherein R1 is selected from phenyl, mono-, di- or tri-substituted phenyl and pyridyl, wherein the substituents on the phenyl are independently selected from F, Cl, Br, I, CN and Ra; and
all other variables are as defined in the first embodiment; or
a pharmaceutically acceptable salt thereof.
A fourth embodiment of the invention is a compound of formula (I), wherein R1 is selected from phenyl, mono-, di- or tri-substituted phenyl and pyridyl, wherein the substituents on the phenyl are independently selected from F, CN and Ra; and
all other variables are as defined in the first embodiment; or
a pharmaceutically acceptable salt thereof.
A fifth embodiment of the invention is a compound of formula (I), wherein R1 is selected from phenyl, mono-, di- or tri-substituted phenyl and pyridyl, wherein the substituents on the phenyl are independently selected from F, CN and Ra;
m is an integer from0 to 1;
L is selected from (CHR2)k, CR8C9(CH2)kxe2x88x921, (CH2)kxe2x88x921CR8R9, and CH2CR8R9CH2;
k is 2 or 3;
each X is independently selected from F. CN and Rh; and
all other variables are as defined in the first embodiment; or
a pharmaceutically acceptable salt thereof
A first class of the invention is a compound of Formula (II): 
wherein R1 is selected from phenyl, mono-, di- or tri-substituted phenyl, pyridyl, and mono-, di-, or tri-substituted pyridyl, wherein the substituents on the phenyl or the pyridyl are independently selected from F, Cl, Br, I, CN, CF3 and Ra;
R10 is selected from H, OH, CN, Rb and ORb;
L is selected from (CH2)k, (CHR2)k, CR8R9(CH2)kxe2x88x921, (CH2)kxe2x88x921CR8R9, CH2CR8R9CH2, CH2CH2CR8R9CH2, and CH2CR8R9CH2CH2;
R2 is Rc;
k is an integer of from 2 to 4;
R5 is selected from H, Re, and (CH2)1-4ORe;
R6 is selected from H and Rf;
R7 is selected from H, Rg, (CH2)1-4ORg, C(xe2x95x90O)ORg and C(xe2x95x90O)Rg;
R8 and R9 are each independently Rc;
each X is independently selected from F, Cl, Br, I, CN and Rh;
Ra, Rc, Re, Rf, Rg and Rh are each independently selected from C1 to C4 alkyl;
Rb is selected from C1 to C6 alkyl and C3 to C7 cyclic alkyl;
and q is an integer of from 0 to 3, provided that when R7 is CORg or COORg, R1 is not phenyl; or
a pharmaceutically acceptable salt thereof.
A second class of the invention is a compound of Formula (II) wherein R1 is selected from phenyl, mono-, di- or tri-substituted phenyl and pyridyl, wherein the substituents on the phenyl are independently selected from F, Cl, Br, I, CN, CF3 and Ra;
R5 is selected from H and Re; and
all other variables are as defined in the first class; or
a pharmaceutically acceptable salt thereof.
A third class of the invention is a compound of Formula (III): 
wherein R1 is 
wherein R12 and R14 are each independently selected from H, F, Cl, Br, I, CN, CF3 and C1 to C4 alkyl;
R10 is selected from H, OH, and Rb;
k is an integer of from 2 to 4;
R5 is selected from H, Re and (CH2)1-4ORe;
R6 is selected from H, methyl and ethyl;
R7 is selected from H, Rg, (CH2)qOR9, C(xe2x95x90O)ORg and C(xe2x95x90O)Rg; provided that when R12 and R14 are both H, R7 is neither C(xe2x95x90O)ORg nor C(xe2x95x90O)Rg;
Rb, Re and Rg are each independently selected from C1 to C4 alkyl; or
a pharmaceutically acceptable salt thereof.
Illustrative of the invention is a compound of Formula (III) wherein R12 and R14 are each independently selected from H, F, CN and C1 to C4 alkyl;
k is an integer of from 2 to 3;
R5 is selected from H, methyl, ethyl, and CH2OCH3;
R7 is selected from H, methyl, ethyl, C(xe2x95x90O)OCH3, and C(xe2x95x90O)CH3; provided that when R12 and R14 are both H, R7 is neither C(xe2x95x90O)OCH3 nor C(xe2x95x90O)CH3; and
all other variables are as defined in the third class; or
a pharmaceutically acceptable salt thereof.
Also illustrative of the invention is a compound of Formula (III) wherein R7 is selected from H, methyl and ethyl; and
all other variables are as defined in the immediately preceding paragraph; or
a pharmaceutically acceptable salt thereof.
Exemplifying the invention is a compound selected from:
(4R)-4-(3,4-Difluorophenyl)-6methoxymethyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid {3-[4(2-cyano-4-fluorophenyl)-piperidin-1-yl]-propyl}-amide;
(4R)-4-(3,4-Difluorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid {3-[4-(2-cyano-4-fluorophenyl)-piperidin-1-yl]-propyl}-amide;
(4R)-4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-1,2,3,4-tetrahydro-pyrirmidine-5-carboxylic acid {3-[4-(2-cyanophenyl)-piperidin-1-yl]-propyl}-amide Hydrochloride.
(4R)-4-(3,4-Difluorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid {3-[4-(2-cyanophenyl)-piperidin-1-yl]-propyl}-amide;
(4R)-4-(3,4-Difluorophenyl)-6methoxymethyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid {3-[4-(4-fluorophenyl)-4-hydroxy-piperidin-1-yl]-propyl}-amide.
(4R)-4-(3,4-Difluorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid {3-[4-(4-fluorophenyl)-4-hydroxy-piperidin-1-yl]-propyl}-amide;
(4R)-4-(3,4-Difluorophenyl)-6methoxymethyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid [3-(3xe2x80x2,4xe2x80x2,5xe2x80x2,6xe2x80x2-tetrahydro-2xe2x80x2H-[2,4xe2x80x2]bipyridinyl-1xe2x80x2-yl)-propyl]-amide dihydrochloride.
(4R)-4-(3,4-Difluorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid [3-(3xe2x80x2,4xe2x80x2,5xe2x80x2,6xe2x80x2-tetrahydro-2xe2x80x2H-[2,4xe2x80x2]bipyridinyl-1xe2x80x2-yl)-propyl]-amide;
(xe2x88x92)-4-(3,4-Difluorophenyl)-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid {3-[4-(2-cyanophenyl)piperidin-1-yl]-propyl}-amide;
(xe2x88x92)-4-(3,4-Difluorophenyl)-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid {3-[4-(4-fluorophenyl)-piperidin-1-yl]-propyl}-amide;
(xe2x88x92)-4-(3,4-Difluorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid [3-[4-(4-fluoropheny1)-piperidin-1-yl]-propyl]-amide;
(xe2x88x92)-4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid {3-[4-(4-fluorophenyl)-pipexidin-1-yl]-propyl}-amide;
(xe2x88x92)-4-(3,4-Difluorophenyl)-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid {3-[4-(4-fluorophenyl)-4-hydroxy-piperidin-1-yl]-propyl}-amide;
(xe2x88x92)-4-(3,4-Difluorophenyl)-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid {3-[4-(2-cyano-4-fluorophenyl)-piperidin-1-yl]-propyl}-amide;
(xe2x88x92)-4-(3,4-Difluorophenyl)-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid [3-(3xe2x80x2,4xe2x80x2,5xe2x80x2,6xe2x80x2-tetrahydro-2xe2x80x2H-[2,4xe2x80x2]bipyridinyl-1xe2x80x2-yl)-propyl]-amide;
(xe2x88x92)-4-(3,4-Difluorophenyl )-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid {3-[4-cyano-4-(fluorophenyl)-piperidin-1-yl]-propyl}-amide;
(xe2x88x92)-4-(3,4-Difluorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid {3-[4-cyano-4-(4-(4-fluorophenyl)-piperidin-1-yl]-propyl}-amide;
(xe2x88x92)-4-(3,4-Difluorophenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid {3-[4-cyano-4-(2-cyanophenyl)-piperidin-1-yl]-propyl}-amide;
4-(3,4-Difluorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid {3-[4-cyano-4-(2-cyanophenyl)-piperidin-1-yl]-propy}-amide;
4-(3,4-Difluorophenyl)-1-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid {3-[4-cyano-4-(2,4-difluorophenyl)-piperidin-1-yl]-propyl}-amide;
(+)-4-(3,4-Difluorophenyl)-1-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid {3-[4-cyano-4-(4-fluorophenyl)-piperidin-1-yl]-propyl}-amide;
4-(3,4-Difluorophenyl)-1-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid {3-[4-(4-fluorophenyl)-piperidin-1-yl]-propyl}-amide;
4-(3,4-Difluorophenyl)-1,3-dimethyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid {3-[4-cyano-4-(4-fluorophenyl)-piperidin-1-yl]-propyl}-amide;
4-(3,4-Difluorophenyl)-1,3-dimethyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid {3-[4-(2-cyano-4-fluorophenyl)-piperidin-1-yl]-propyl}-amide;
4-(3,4-Difluorophenyl)-1,3-dimethyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid {3-[4-(4-fluorophenyl)-piperidin-1-yl]-propyl}-amide;
4-(3,4-Difluorophenyl)-1,3-dimethyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid {3-[4-cyano-4-(2,4-difluorophenyl)-piperidin-1-yl]-propyl}-amide;
4-(3,4-Difluorophenyl)-1-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid {3-[4-(4-fluorophenyl)-4-hydroxy-piperidin-1-yl]-propyl}-amide;
4-(3,4-Difluorophenyl)-1-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid {3-[4-(2-cyanr4-fluorophenyl)piperidin-1-yl]-propyl}-amide;
(xe2x88x92)-4-(3,4-Difluorophenyl)-1-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid {3-[4-cyano-4-(4-fluorophenyl)pipendin-1-yl]-propyl}-amide;
4-(3,4-Difluorophenyl)-1-methyl-2-oxo -1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid {3-[2-cyano-4-fluorophenyl)-4-cyano-piperidin-1-yl]-propyl}amine;
4-(3,4-Difluorophenyl)-1,3-dimethyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5- carboxylic acid {3-[2-cyano-4-fluorophenyl)-4-cyanopiperidin-1-yl]-propyl}amine;
4-(3,4-Difluorophenyl)-1,6-dimethyl-2-oxo -1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid {3-[2-cyano-4-fluorophenyl)-piperidin-1-yl]-propyl}amine;
4-(3,4-Difluorophenyl)-1,6-dimethyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid {3-[4-(4-fluorophenyl)-piperidine-1-yl]-propyl}-amide;
(4R)-4-(3,4-Difluorophenyl)-1,6-dimethyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid {3-[4-(4-fluorophenyl)-4-cyano-piperidine-1-yl]-propyl}-amide;
(4R)-4-(3,4-Difluorophenyl)-1,6-dimethyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid {3-[4-(2,4-difluorophenyl)-4-cyano-piperidine-1-yl]-propyl}-amide;
4-(3,4-Difluorophenyl)-1,3,6-tzimethyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid-{3-[4-(4-fluorophenyl)-piperidin-1-yl]-propyl}-amide;
(4R)-4-(3,4-Difluorophenyl)-1,3,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid {3-[4-(4-fluorophenyl)-4-cyano-piperidin-1-yl]-propyl}-amide;
(4R)-4-(3,4-Difluorophenyl)-1,3,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid {3-[4-(2,4-difluorophenyl)-4-cyano-piperidine-1-yl]-propyl}-amide;
4-(3,4-Difluorophenyl)-1,6-dimethyl-3-acetyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid {3-[4-(4-fluorophenyl)-piperidin-1-yl]-propyl}-amide;
4-(3,4-Difluorophenyl)-1,6-dimethyl-3-carbomethoxy-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid {3-[4-(4-fluorophenyl)-piperidine-1-yl]-propyl}amide;
(xe2x88x92)-4-(3,4-Difluorophenyl)-3,6-dimethyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid {3-[4-(2-cyano-4-fluorophenyl)-piperidin-1-yl]-propyl}-amide;
(xe2x88x92)-4-(3,4-Difluorophenyl)-3,6-dimethyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid {3-[4-cyano-4-(4-fluorophenyl)-piperidin-1-yl]-propyl}-amide;
(xe2x88x92)-4-(3,4-Difluorophenyl)-3,6-dimethyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid {3-[4-cyano-4-(2,4-difluorophenyl)-piperidin-1-yl]-propyl}-amide;
(xe2x88x92)-4-(3,4-Difluorophenyl)-3,6-dimethyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid {3-[4-(4-fluorophenyl)-piperidin-1-yl]-propyl}-amide;
(xe2x88x92)-4-(3,4-Difluorophenyl)-1,6-dtimethyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid {3-[4-(2-cyano-4-fluorophenyl)-piperidin-1-yl]-propyl}-amide;
(xc2x1)-4-(3,4-Difluorophenyl)-1,3,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid {3-[4-(2-cyano-4-fluorophenyl)-piperidin-1-yl]-propyl}-amide;
(xe2x88x92)-4-(3,4-Difluorophenyl)-1,3,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid {3-[4-(2-cyano-4-fluorophenyl)-piperidin-1-yl]-propyl}-amide;
(+)-4-(3,4-Difluorophenyl)-1,3,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid {3-[4-(2-cyano-4-fluorophenyl)-piperidin-1-yl]-propyl}-amide;
(4R)-4-(3,4-Difluorophenyl)-6methoxymethyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid {3-[4-cyano-4-(4-fluorophenyl)-piperidin-1-yl]-propyl}-amide;
(4R)-4-(3,4-Difluorophenyl)-6methoxymethyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid {3-[4-cyano-4-(2,4-difluorophenyl)-piperidin-1-yl]-propyl}-amide;
(4R)-4-(3,4-Difluorophenyl)-6-methoxymethyl-1-methyl-2-oxo-1,2,3,4-tetrahydro-pyzimidine-5-carboxylic acid {3-[4-cyano-4-(4-fluorophenyl)-piperidin-1-yl]-propyl}-amide;
4-(3,4-Difluorophenyl)-6-methoxymethyl-1-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid {3-[4-(4-fluorophenyl)-piperidin-1-yl]-propyl}-amide;
and pharmaceutically acceptable salts thereof.
In a preferred embodiment of the invention, the compound is Compound A, which is 
or a pharmaceutically acceptable salt thereof.
Another aspect of the invention is a pharmaceutical composition comprising a therapeutically effective amount of any of the compounds described above and a pharmaceutically acceptable carrier. One embodiment is a pharmaceutical composition made by combining any of the compounds described above and a pharmaceutically acceptable carrier. Another embodiment is a process for making a pharmaceutical composition comprising combining any of the compounds described above and a pharmaceutically acceptable carrier.
Still another aspect of the invention is the pharmaceutical composition described in the preceding paragraph further comprising a therapeutically effective amount of a testosterone 5-alpha reductase inhibitor. In a preferred embodiment, the testosterone 5-alpha reductase inhibitor is a type 1, a type 2, both a type 1 and a type 2 (i.e., a three component combination comprising any of the compounds described above combined with both a type 1 testosterone 5-alpha reductase inhibitor and a type 2 testosterone 5-alpha reductase inhibitor) or a dual type 1 and type 2 testosterone 5-alpha reductase inhibitor. In a more preferred embodiment, the testosterone 5-alpha reductase inhibitor is a type 2 testosterone 5-alpha reductase inhibitor. Most preferably, the testosterone 5-alpha reductase inhibitor is finasteride.
A further aspect of the invention is a method of treating benign prostatic hyperplasia in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of any of the compounds (or any of the compositions) described above. In one embodiment of the method of treating BPH, the compound (or composition) additionally does not cause a fall in blood pressure at dosages effective to alleviate BPH. In another embodiment of the method of treating BPH, the compound is administered in combination with a testosterone 5-alpha reductase inhibitor. A preferred testosterone 5-alpha reductase inhibitor for use in the method is finasteride.
Yet another aspect of the invention is a method of inhibiting contraction of prostate tissue or relaxing lower urinary tract tissue in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of any of the compounds (or any of the compositions) described above. In one embodiment of the method of inhibiting contraction of prostate tissue or relaxing lower urinary tract tissue, the compound (or composition) additionally does not cause a fall in blood pressures at dosages effective to inhibit contraction of prostate tissue. In another embodiment, the compound (or composition) is administered in combination with a testosterone 5-alpha reductase inhibitor; preferably, the testosterone 5-alpha reductase inhibitor is finasteride.
A further aspect of the invention is a method of treating a disease which is susceptible to treatment by antagonism of the alpha 1a receptor which comprises administering to a subject in need thereof an amount of any of the compounds described above effective to treat the disease. Diseases which are susceptible to treatment by antagonism of the alpha 1a receptor include, but are not limited to, BPH, high intraocular pressure, high cholesterol, impotency, sympathetically mediated pain, migraine (see K.A. Vatz, Headache, Vol. 37, 107-108 (1997)) and cardiac arrhythmia.
An additional aspect of the invention is the use of any of the compounds described above in the preparation of a medicament for: a) treating benign prostatic hyperplasia; b) relaxing lower urinary tract tissue; or c) inhibiting contraction of prostate tissue; in a subject in need thereof.
A further aspect of the invention is the use of any of the alpha 1a antagonist compounds described above and a 5-alpha reductase inhibitor for the manufacture of a medicament for: a) treating benign prostatic hyperplasia; b) relaxing lower urinary tract tissue; or c) inhibiting contraction of prostate tissue which comprises an effective amount of the alpha 1a antagonist compound and an effective amount of 5-alpha reductase inhibitor, together or separately.
These and other embodiments, aspects and features of the present invention are either further described in or will be apparent from the ensuing description, examples and appended claims.
The compounds of the invention are 5-carboxamide substituted dihydropyrimidin-2-ones in which the carboxamide substituent contains a saturated, nitrogen-containing heterocyclic ring. These may be generally referred to as xe2x80x9creverse dihydropyrimidinonesxe2x80x9d to distinguish them from dihydropyrimidin-2-ones having analogous carboxamide substituents on one of the pyrimidinone nitrogens instead of the ring-5 carbon atom. The compound of the present invention is a compound of Formula (I) as set forth above. In Formula (I), R1 is suitably selected from phenyl, substituted phenyl, pyridyl and substituted pyridyl. R1 is typically selected from phenyl, mono-, di-, or tri-substituted phenyl, pyridyl and mono-, di- or tri-substituted pyridyl. In other embodiments, R1 is selected from phenyl, mono-, di or tri-substituted phenyl, and pyridyl; or from phenyl, mono- or di-substituted phenyl, and pyridyl. It is understood that when R7 is either C(xe2x95x90O)ORg or C(xe2x95x90O)Rg, R1 is not phenyl. In other words, when R7 is either C(xe2x95x90O)ORg or C(xe2x95x90O)ORg, R1 is selected from substituted phenyl, pyridyl, and substituted pyridyl.
The substituents on the substituted phenyl or substituted pyridyl are each independently selected from F, Cl, Br, I, (CH2)0-4CF3, CN, NO2, Ra and ORa. More typically the substituents are independently selected from F, Cl, Br, I, CN, Ra, ORa, and (CH2)0-2CF3. In other embodiments, the substituents are selected from F, CN, Ra, ORa, and (C112)0-2CF3; or from F, CN, Ra, and CF3; or from F and CN.
In a preferred embodiment, R1 is 
wherein R12 and R14 are each independently selected from H, F, Cl, Br, C, CN, C1 to C4 alkyl and CF3. In other embodiments R12 and R14 are each independently selected from H, F, CN, C1 to C4 alkyl and CF3; or from H, F, CN and C1 to C4 alkyl; or from H, F, CN, methyl and ethyl; or from H, F, CN; or from H and F. It is understood that R8 and R9 are not both H, when R7 (defined elsewhere) is either C(xe2x95x90O)ORg or C(xe2x95x90O)Rg.
R10 is suitably selected from H, OH, CN, Rb, ORb, (CH2)1-4ORb and (CH2)0-4CF3. R10 is typically selected from H, OH, CN, Rb, ORb, (CH2)1-2ORb and (CH2)0-1CF3. In other embodiments, R10 is selected from H, OH, CN, Rb, ORb and CF3 or from H, OH, CN, Rb and ORb; or from H, OH, Rb, and ORb; or from H and CN; or from H and OH.
m is an integer from 0 to 2; preferably an integer from 0 to 1 (i.e., the heterocyclic ring is either pyrrolidinyl or piperidinyl); and more preferably is 1 (i.e., the ring is piperidinyl).
L is selected from (CH2)k, (CHR2)k, CR8R9(CH2)kxe2x88x921, (CH2)kxe2x88x921OCR8R9, CH2CR8R9CH2, CH2CH2CR8R9CH2, and CH2CR8R9CH2CH2. In a preferred embodiment L is selected from (CH2)k and (CHR2)k. In a more preferred embodiment, L is (CH2)k.
R2 is selected from Rc and (CH2)0-4CF3. More typically R2 is Rc. In other embodiments, R2 is selected from Rc and (CH2)0-2CF3; or from Rc and CF3.
R8 and R9 are each independently selected from Rc and (CH2)0-4CF3. More typically R8 and R9 are independently Rc. In other embodiments, R8 and R9 are independently selected from Rc and (CH2)0-4CF3; or from Rc and CF3.
k is suitably an integer of from 2 to 4, and is typically an integer of from 2 to 3. In one embodiment, k=3.
R4 is suitably selected from H, Rd and (CH2)0-4CF3, and is typically selected from H, Rd and (CH2)0-2CF3. In other embodiments, R4 is selected from H, Rd and CF3; or from H and Rd. In a preferred embodiment R4=H.
R5 is suitably selected from H, Re, (CH2)1-4ORe and (CH2)1-4CF3; and is typically selected from H, Re, (CH2)1-2ORe and (CH2)1-2CF3. In other embodiments, R5 is selected from H, Re and (CH2)1-4ORe; or from H and Re.
R6 is suitably selected from H and Rf.
R7 is suitably selected from H, Rg, (CH2)1-4ORg, C(xe2x95x90O)OR9, C(xe2x95x90O)Rg and (CH2)0-4CF3; and is typically selected from H, Rg, (CH2)1-2ORg, C(xe2x95x90O)OR9, C(xe2x95x90O)Rg and (CH2)0-4CF3. In other embodiments, R7 is selected from H, Rg, (CH2)1-4ORg, C(xe2x95x90O)ORg and C(xe2x95x90O)Rg; or from H, Rg and (CH2)1-4ORg; or H and Rg.
Each X is independently selected from F, Cl, Br, I, CN and Rh. In other embodiments, each X is independently selected from F, CN and Rh; or from F and CN. In a preferred embodiment each X is F.
q is an integer of from 0 to 4, and preferably 0 to 3. In other embodiments, q is 1 or 2; or is 2.
Ra, Rd, Rc, Rf, Rg and Rh are suitably each independently selected from C1 to C6 alkyl, and typically are each independently selected from C1 to C4 alkyl. In a preferred embodiment, each of Ra, Rd, Re, Rf, Rg and Rh is independently selected from methyl and ethyl.
Rb and Rc are suitably each independently selected from C1 to C6 alkyl and C3 to C7 cyclic alkyl; and typically selected from C1 to C4 alkyl and C3 to C6 cyclic alkyl. In other embodiments, Rb and Rc are each independently selected from C1 to C6 alkyl and C3 to C7 cycloalkyl; or from C1 to C4 alkyl and C3 to C6 cycloalkyl; or from C1 to C4 alkyl.
The term xe2x80x9cC1 to C6 alkylxe2x80x9d means linear or branched chain alkyl groups having from 1 to 6 carbon atoms and includes all of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl. xe2x80x9cC1 to C4 alkylxe2x80x9d means n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl.
The term xe2x80x9cC3 to C7 cyclic alkylxe2x80x9d means cycloalkyl rings having from 3 to 7 carbon atoms (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl) optionally substituted with one or more C1 to C6 alkyl groups as defined above.
The term xe2x80x9carylxe2x80x9d as used herein, except where otherwise specifically defined, refers to phenyl or substituted phenyl.
The term xe2x80x9csubstitutedxe2x80x9d includes multiple degrees of substitution by a named substituent to the extent such multiple substitution is chemically allowed. Thus, for example, xe2x80x9csubstituted phenylxe2x80x9d includes mono-, di- tri-, tetra- and penta-substituted phenyl groups.
The definition of any substituent or variable (e.g., X or Rc) at a particular location in a molecule is independent of its definitions elsewhere in that molecule. Thus, CR8R9(CH2)kxe2x88x921, wherein k=2 and R8 and R9 are each independently Rc, represents 
It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth below.
Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally.
Representative compounds of the present invention exhibit high selectivity for the human alpha 1a adrenergic receptor. One implication of this selectivity is that these compounds display selectivity for lowering intraurethral pressure without substantially affecting diastolic blood pressure.
Representative compounds of this invention display submicromolar affinity for the human alpha 1a adrenergic receptor subtype while displaying at least ten-fold lower affinity for the human alpha 1d and alpha 1b adrenergic receptor subtypes, and many other G-protein coupled human receptors. Particular representative compounds of this invention exhibit nanomolar and subnanomolar affinity for the human alpha 1a adrenergic receptor subtype while displaying at least 30 fold lower affinity for the human alpha 1d and alpha 1b adrenergic receptor subtypes, and many other G-protein coupled human receptors (e.g., serotonin, dopamine, alpha 2 adrenergic, beta adrenergic or muscarinic receptors). Still other representative compounds of this invention exhibit nanomolar and subnanomolar affinity for the human alpha 1a adrenergic receptor subtype while displaying at least 50 fold lower affinity for the human alpha 1d and alpha 1b adrenergic receptor subtypes, and many other G-protein coupled human receptors (e.g., serotonin, dopamine, alpha 2 adrenergic, beta adrenergic or muscarinic receptors).
These compounds are administered in dosages effective to antagonize the alpha 1a receptor where such treatment is needed; e.g., treatment of BPH. For use in medicine, the salts of the compounds of this invention refer to non-toxic xe2x80x9cpharmaceutically acceptable salts.xe2x80x9d Other salts may, however, be useful in the preparation of the compounds according to the invention or in the prepartion of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts. Thus, representative pharmaceutically acceptable salts include the following:
Acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium, canmsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, n-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate.
Compounds of this invention are used to reduce the acute symptoms of BPH. Thus, compounds of this invention may be used alone or in combination with more long-term anti-BPH therapeutics, such as testosterone 5-a reductase inhibitors, including PROSCAR(copyright) (finasteride). Aside from their utility as anti-BPH agents, these compounds may be used to induce highly tissue-specific, localized alpha 1a adrenergic receptor blockade whenever this is desired. Effects of this blockade include reduction of intra-ocular pressure, control of cardiac arrhythmias, and possibly a host of alpha 1a receptor mediated central nervous system events.
The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds of this invention which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term xe2x80x9cadministeringxe2x80x9d shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985. Metabolites of these compounds include active species produced upon introduction of compounds of this invention into the biological milieu.
Where the compounds according to the invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds according to the invention possess two or more chiral centers, they may additionally exist as diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents. Such solvates are also encompassed within the scope of this invention.
The term xe2x80x9cselective alpha 1a adrenergic receptor antagonist,xe2x80x9d as used herein, refers to an alpha 1a antagonist compound which is at least ten fold selective for the human alpha 1a adrenergic receptor as compared to the human alpha 1b, alpha 1d, alpha 2a, alpha 2b and alpha 2c adrenergic receptors.
The term xe2x80x9clower urinary tract tissue,xe2x80x9d as used herein, refers to and includes, but is not limited to, prostatic smooth muscle, the prostatic capsule, the urethra and the bladder neck.
The term xe2x80x9csubject,xe2x80x9d as used herein refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d as used a herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease being treated.
The present invention includes pharmaceutical compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the compositions may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
As used herein, the term xe2x80x9ccompositionxe2x80x9d encompasses a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
The liquid forms in which the novel compositions of the present invention may be incorporated for a ministration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
Where the processes for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (xe2x88x92)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-1-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known in the art.
The specificity of binding of compounds showing affinity for the alpha 1a receptor is shown by comparing affinity to membranes obtained from transfected cell lines that express the alpha 1a receptor and membranes from cell lines or tissues known to express other types of alpha (e.g., alpha 1d, alpha 1b) or beta adrenergic receptors. Expression of the cloned human alpha 1d, alpha 1b, and alpha 1a receptors and comparison of their binding properties with known selective antagonists provides a rational way for selection of compounds and discovery of new compounds with predictable pharmacological activities. Antagonism by these compounds of the human alpha 1a adrenergic receptor subtype may be functionally demonstrated in anesthetized animals. These compounds may be used to increase urine flow without exhibiting hypotensive effects.
The ability of compounds of the present invention to specifically bind to the alpha 1a receptor makes them useful for the treatment of BPH. The specificity of binding of compounds showing affinity for the alpha 1a receptor is compared against the binding affinities to other types of alpha or beta adrenergic receptors. The human alpha adrenergic receptor of the 1a subtype was recently identified, cloned and expressed as described in PCT International Application Publication Nos. WO94/08040, published Apr. 14, 1994 and WO 94/21660, published Sep. 29, 1994. The cloned human alpha 1a receptor, when expressed in mammalian cell lines, is used to discover ligands that bind to the receptor and alter its finction. Expression of the cloned human alpha 1d, alpha 1b, and alpha 1a receptors and comparison of their binding properties with known selective antagonists provides a rational way for selection of compounds and discovery of new compounds with predictable pharmacological activities.
Compounds of this invention exhibiting human alpha 1a adrenergic receptor antagonism may further be defined by counterscreening. This is accomplished according to methods known in the art using other receptors responsible for mediating diverse biological functions. [See e.g., PCT International Application Publication No. WO94/10989, published May 26, 1994; U.S. Pat. No. 5,403,847, issued Apr. 4, 1995]. Compounds which are both selective amongst the various human alpha1 adrenergic receptor subtypes and which have low affinity for other receptors, such as the alpha 2 adrenergic receptors, the xcex2-adrenergic receptors, the muscarinic receptors, the serotonin receptors, and others are particularly preferred. The absence of these non-specific activities may be confirmed by using cloned and expressed receptors in an analogous fashion to the method disclosed herein for identifying compounds which have high affinity for the various human alpha1 adrenergic receptors. Furthermore, functional biological tests are used to confirm the effects of identified compounds as alpha 1a adrenergic receptor antagonists.
The present invention also has the objective of providing suitable topical, oral, systemic and parenteral pharmaceutical formulations for use in the novel methods of treatment of the present invention. The compositions containing compounds of this invention as the active ingredient for use in the specific antagonism of human alpha 1a adrenergic receptors can be administered in a wide variety of therapeutic dosage forms in conventional vehicles for systemic administration. For example, the compounds can be administered in such oral dosage forms as tablets, capsules (each including timed release and sustained release formulations), pills, powders, granules, elixirs, tinctures, solutions, suspensions, syrups and emulsions, or by injection. Likewise, they may also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous, topical with or without occlusion, or intramuscular form, all using forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the compound desired can be employed as an alpha 1a antagonistic agent.
Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
The dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic finction of the patient; and the particular compound thereof employed. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition. Optimal precision in achieving concentration of drug within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug""s availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of a drug.
In the methods of the present invention, the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as xe2x80x9ccarrierxe2x80x9d materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include, without limitation, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
The liquid forms in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like. Other dispersing agents which may be employed include glycerin and the like. For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.
The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxy-ethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydro-pyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
Compounds of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever specific blockade of the human alpha 1a adrenergic receptor is required.
The daily dosage of the products may be varied over a wide range; e.g., from about 0.01 to about 1000 mg per adult human per day. For oral administration, the compositions are preferably provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0 and 100 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably, from about 1 mg to about 100 mg of active ingredient. An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.0002 mg/kg to about 20 mg/kg of body weight per day. Preferably, the range is from about 0.001 to about 10 mg/kg of body weight per day, and especially from about 0.001 mg/kg to about 7 mg/kg of body weight per day. The compounds may be administered on a regimen of 1 to 4 times per day.
Compounds of this patent disclosure may be used alone at appropriate dosages defined by routine testing in order to obtain optimal antagonism of the human alpha 1a adrenergic receptor while minimizing any potential toxicity. In addition, co-administration or sequential administration of other agents which alleviate the effects of BPH is desirable. Thus, in one embodiment, this invention is administration of compounds of this invention and a human testosterone 5-a reductase inhibitor. Included with this embodiment are inhibitors of 5-alpha reductase isoenzyme 2. Many such compounds are now well known in the art and include such compounds as PROSCAR(copyright), (also known as finasteride, a 4-Aza-steroid; see U.S. Pat. Nos. 4,377,584 and 4,760,071, for example). In addition to PROSCAR(copyright), which is principally active in prostatic tissue due to its selectivity for human 5-a reductase isozyme 2, combinations of compounds which are specifically active in inhibiting testosterone 5-alpha reductase isozyme 1 and compounds which act as dual inhibitors of both isozymes 1 and 2, are useful in combination with compounds of this invention. Compounds that are active as 5a-reductase inhibitors have been described in WO93/23420, EP 0572166; WO 93/23050; WO93/23038; WO93/23048; WO93/23041; WO93/23040; WO93/23039; WO93/23376; WO93/23419, EP 0572165; WO93/23051.
The dosages of the alpha 1a adrenergic receptor and testosterone 5-alpha reductase inhibitors are adjusted when combined to achieve desired effects. As those skilled in the art will appreciate, dosages of the 5-alpha reductase inhibitor and the alpha 1a adrenergic receptor antagonist may be independently optimized and combined to achieve a synergistic result wherein the pathology is reduced more than it would be if either agent were used alone. In accordance with the method of the present invention, the individual components of the combination can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. The instant invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term xe2x80x9cadministeringxe2x80x9d is to be interpreted accordingly.
Thus, in one preferred embodiment of the present invention, a method of treating BPH is provided which comprises administering to a subject in need of treatment any of the compounds of the present invention in combination with finasteride effective to treat BPH. The dosage of finasteride administered to the subject is about 0.01 mg per subject per day to about 50 mg per subject per day in combination with an alpha 1a antagonist. Preferably, the dosage of finasteride in the combination is about 0.2 mg per subject per day to about 10 mg per subject per day, more preferably, about 1 to about 7 mg per subject to day, most preferably, about 5 mg per subject per day.
For the treatment of benign prostatic hyperplasia, compounds of this invention exhibiting alpha 1a adrenergic receptor blockade can be combined with a therapeutically effective amount of a 5a-reductase 2 inhibitor, such as finasteride, in addition to a 5a-reductase 1 inhibitor, such as 4,7xcex2-dimethyl-4-aza-5a-cholestan-3-one, in a single oral, systemic, or parenteral pharmaceutical dosage formulation. Alternatively, a combined therapy can be employed wherein the alpha 1a adrenergic receptor antagonist and the 5a-reductase 1 or 2 inhibitor are administered in separate oral, systemic, or parenteral dosage formulations. See, e.g., U.S. Pat. No.""s 4,377,584 and 4,760,071 which describe dosages and formulations for 5a-reductase inhibitors.
Abbreviations used in the instant specification, particularly the Schemes and Examples, are as follows:
AcOH or HOAc=acetic acid
BCE-BOCA=bis-(2-chloroethyl)-tert-butoxycarbonylamine
BF3 Et2O=boron trifluoride diethyl etherate
Boc or BOC=t-butyloxycarbonyl
Boc2O=di-tert-butyl dicarbonate
DBU=1,8-diazabicyclo[5.4.0]undec-7-ene
DfBzCHO=3,4-difluorobenzaldehyde
DMF=N,N-dimethylformamide
DMSO=dimethylsulfoxide
EDC=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
Et=ethyl
Et3N=triethylamine
EtOAc=ethyl acetate
EtOH=ethanol
HOAt=1-hydroxy-7-azabenzotriazole
HOBt=1-hydroxy benzotriazole hydrate
HPLC=high performance liquid chromatography
LDA=lithium diisopropylamide
Me=methyl
MeI=methyl iodide
MeOH=methanol
NMR=nuclear magnetic resonance
NPhCF=p-nitrophenylchoroformate
OMe=methoxy
Pd/C=palladium on carbon
TEA=triethylamine
THF=tetrahydrofuran
TLC=thin layer chromatography
The compounds of the present invention can be prepared readily according to the following reaction schemes and examples, or modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail. Unless otherwise indicated, all variables are as defined above.
Many of the compounds of the present invention can be prepared as outlined in Scheme 1. Reaction of 1-Boc-4-piperidone with LDA and n-phenyltrifluoromethane sulfonimide provides the 1,2,5,6-tetrahydropyridin-4-yl ester of trifluoromethane sulfonic acid which, upon reaction with aryl zinc iodide in the presence of tetrakis (triphenylphosphine) palladium provides 1-Boc-4-aryl-1,2,5,6-tetrahydropyridine which is hydrogenated to 1-Boc-4-arylpiperidine. The Boc group is then removed by reaction with HCl to form the 4-aryl piperiidinium hydrochloride. The hydrochloride is then reacted with 3-bromo-1-Boc-propylamine and TEA to provide 3-[4-aryl piperidin-1-yl]-1-Boc-propylamine, which is converted to the hydrochloride by reaction with HCl. The hydrochloride is then reacted with a 5-carboxylic acid dihydropyrimidin-2-one (e.g., 4-difluorophenyl-6-alkoxyalkyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid), EDC, HOBT and TEA to obtain 5-(3-[4-arylpiperidin-1-yl]-propyl) carboxamido-1,6-dihydropyrimidin-2-one (e.g., 4-difluorophenyl-6-alkoxyalkyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid [3-(4-arylpiperidin-1-yl) propyl]-amide).
Scheme 2 is a variation of Scheme 1 by which 4-aryl-hydropiperidin-1-yl substituents can be obtained. An arylmagnesium bromide is reacted with 1-Boc-4-piperidone to obtain 1-Boc-4-aryl-4-hydroxy piperidine which is converted to the hydrochloride salt by reation with HCl. This 4-aryl-4-hydroxy hydrochloride is then reacted in the same manner as the 4-aryl piperidine hydrochloride in Scheme 1 to obtain the 5-[3-[-4-hydroxy-4-arylpiperidin-1-]-propyl]carboxamide-1,6-dihydropyridin-2-one (e.g., 4-difluorophenyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid [3-(4-hydroxy-4-arylpiperidin-1-yl) propyl]amide).
Scheme 3 provides a general method for preparing the reverse dihydropyrimidinones of the invention with 4-aryl-4-cyanopiperidin-1-yl substituents. Arylacetonitrile is reacted with BCEBOCA and NaH or CsCO3 to provide 1-Boc-4-aryl-4-cyano-piperidine, which is converted to 4-aryl-4-cyano-piperidine hydrochloride by reaction with HCl. This hydrochloride is then reacted in the same manner as the 4-arylpiperidum hydrochloride in Scheme 1 to obtain the 5-{3-[4cyano-4-aryl-piperidin-1-yl]-propyl} carboxamide-1,6-dihydropyrimidin-2-one (e.g., 4-difluorophenyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid-[3-(4-cyano-4-arylpiperidin-1-yl) propyl]amide).
Schemes 4-6 present general procedures for preparing the 5-carboxylic acid dihydropyrimidin-2-one intermediates employed in Schemes 1-3. In both Schemes 4 and 5, methyl-3,3-dimethoxypropionate is condensed with urea (or an alkylurea) and an arylaldehyde catalyzed by acetic acid, copper oxide and a Lewis acid (e.g., BF3⊚Et2O) to obtain 4-aryl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid methyl ester from urea (or the 1-alkyl analog from alkylurea), which is subsequently converted to the 5-carboxylic acid derivative by basic hydrolysis. Alternatively, the methyl ester can first be treated with an alkyl halide (e.g., methyl iodide) to obtain 4-aryl-3-alkyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester from urea (or the 1-alkyl analog from alkylurea), which is then hydrolyzed to the 5-carboxylic acid derivative. Scheme 4 illustrates the foregoing procedure wherein the urea is alkylurea and the arylaldehyde is 3,4-difluorobenzaldehyde. Scheme 5 illustrates the procedure using methylurea and 3,4-difluorobenzaldehyde.
Scheme 5 also includes a procedure for resolving the optical isomers, wherein the mixture of methyl ester enantiomers is reacted with LDA and NPhCF followed by R-(+) alpha methyl benzylamine to obtain the 3-(1-phenylethyl-carbamoyl) diastereomers, which are separated by conventional means known in the art. The enantiomers are then obtained from the separated diastereomers first by reaction with DBU to regenerate the methyl ester, followed directly by basic hydrolysis to obtain a 4-aryl-2-oxo-1-alkyl-1,2,3,4-tetrahydropyrimidine 5-carboxylic acid enantiomer, or followed by reaction with an alkyl halide and then hydrolysis to obtain a 4-aryl-3-alkyl-2-oxo-1,2,3,4-tetrahydropyrimidine carboxylic acid enantiomer.
Scheme 6 outlines a route to a mixture of 6-alkyl-4-aryl-3-alkyl-2-oxo- and 6-alkyl-4aryl-2-oxo-1-alkyl-1,2,3,4-tetrahydropyrimidine 5-carboxylic acids by N-alkylating 4-aryl-2-methoxy-3,4-dihydropyrimidine 5-carboxylic acid methyl ester with an alkyl halide in the presence of a hydride, followed by acid hydrolysis to form the 2-oxo group, and then by basic hydrolysis to form the 5-carboxylic acid derivative. 